Method of performing a plurality of synthesis processes of preparing a radiopharmaceutical in series, a device and cassette for performing this method

ABSTRACT

A method of performing a plurality of synthesis processes of preparing a radiopharmaceutical in series includes carrying out a first synthesis run including the steps of: a) providing water containing fluorine-18; b) trapping the fluorine-18 from the water provided in step a) on an anion exchange material; c) eluting the trapped fluorine-18 from the anion exchange material to a reaction vessel of first radiopharmaceutical synthesis cassette; d) preparing a radiopharmaceutical incorporating the eluted fluorine-18 using the first radiopharmaceutical synthesis cassette; where steps a)-d) are repeated in at least one subsequent run using another radiopharmaceutical synthesis cassette; and where the method includes a reconditioning step of the anion exchange material between two consecutive runs. A device for performing this method and a cassette for use in the device are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No.PCT/EP2016/061319 filed May 19, 2016, which claims the benefit ofNetherlands Application No. NL 2014828, filed May 20, 2015, the contentsof which is incorporated by reference herein.

FIELD OF THE INVENTION

The invention relates to a method of performing a plurality of synthesisprocesses of preparing a radiopharmaceutical in series, a device forperforming this method and a cassette for use in the method.

BACKGROUND OF THE INVENTION

Radioisotopes for PET (Positron Emission Tomography) are generallyproduced using a cyclotron. In the cyclotron charged particles areaccelerated thereby gaining energy. Upon exiting the cyclotron theaccelerated particles hit a target thereby producing positron emitters.Fluorine-18 (hereinafter 18F) is produced by proton bombardment ofoxygen-18 water (H₂ ¹⁸O). The proton interacts with the 18O and producesa neutron and 18F. The thus produced 18F is allowed to react with asuitable starting material, thereby producing an appropriate tracer(radiopharmaceutical) for diagnosis purposes such as cancer and braindisorders.

Many synthetic routes to prepare PET radiopharmaceuticals have beendeveloped during recent decades. The great majority of PET tracers arelabelled with the positron-emitting radioisotopes 11C and 18F(radioactivity decay: half-lives of 20 and 110 min, respectively). For18F based radiopharmaceuticals production two preparation methods havebeen developed and used throughout the world, electrophilic andnucleophilic 18F fluorination. These reactions are usually performed ina so called synthesizer. Today commercially available synthesizers arehighly automated devices for the production of the tracer, wherein thedirect involvement of operating staff and exposure to radiation isreduced in order to protect them against radiation.

After irradiation the produced 18F in a 18O enriched water solution isusually passed to an anion exchange material, where the 18F is trapped.The 18O water is collected. Subsequently the 18F is eluted usingtypically an eluent like K₂CO₃. K18F is not soluble in organic solventsthat are suitable for performing the subsequent nucleophilic reactionsteps. Therefore a so called phase transfer agent is also added. Typicalexamples thereof include tetra alkyl ammonium salts or aminopolyethers,like Kryptofix®. As fluoride is reactive in water-free media only, anyremaining water is usually removed in one of more evaporation steps,typically using dry acetonitrile under a flow of inert gas like heliumor nitrogen. The 18F once dried and solubilised in the presence of thephase transfer agent is ready for the main nucleophilic substitutionsteps. In the production of 18F-FDG (F-18 fluoro-2-deoxyglucose)typically a precursor is added like mannose triflate. This compound hasa triflate group as a suitable leaving group, while the acetyl groupsensure that fluorination only occurs at the position of the triflategroup. This reaction step is usually carried out at elevated temperaturelike 80-90° C. In the next step the protective acetyl groups are removedby hydrolysis. Both basic hydrolysis typically using NaOH and acidhydrolysis using HCl can be employed. Basic hydrolysis has the advantagethat it can be carried out at room temperature in a short time interval,whereas acid hydrolysis frequently requires a substantial highertemperature and lasts longer. Finally the thus produced 18F-FDG ispurified, which is commonly performed using several purification stepsusing different chromatographic materials.

The synthesizers used can be classified into two categories. A firstcategory comprises stationary systems without any removable components.All connections, tubing, valves, vessels are permanently installed.After completion of a production run, the components are rinsed in a CIP(Clean-In-Place) operation. Although this kind of synthesizers is saidto have the advantage of cost savings due to reusing its components,complete cleaning and sterilization may be difficult to achieve.Moreover, a full CIP operation may be lengthy, resulting in a seriousdowntime of the synthesizer. Additionally waste volumes resulting fromthe CIP operation may be relatively high. Also a cleaning operation maylead to a drop of labelling yield. Typically such a stationary system isdedicated to the production of a single radiopharmaceutical, because itsconfiguration cannot be easily adapted to allow production of anothertracer.

A second category comprises synthesizers which are based on the use ofremovable kits or cassettes. In some cassettes the reagents need to beactivated prior to use. Other cassettes are ready-to-use and need onlyto be inserted. All process steps including prior testing sequences andrelated process parameters and other data are predetermined and part ofthe software, which is installed in a suitable programmable logicalcontroller (PLC), server or PC. Each synthesizer has its own PC, routerand PLC, or customized electronic board. Principally cassette basedsynthesizers are useful for performing subsequent syntheses, whichdepending on the selected cassette, reagents kits and software mayproduce different radiopharmaceuticals.

In view of radiation protection (radio-safety) synthesizers areinstalled in a so called hot cell, a protective shielding typically madefrom lead. The size and amount of shielding is mainly dependent on thedimensions and configuration of the synthesizer. Thus compactness of thesynthesizer is highly desirable in view of costs and weight of theshielding. After a production run, the device contains still radioactiveresidues, so that manually handling the synthesizer is dangerous. Decayperiods of more than 12 hours are likely to be observed, before theresidual activity on the spent cassette has dropped below a certainlimit and the synthesizer can be accessed safely. This is a seriousdrawback if multiple batches are to be produced during a single day.

Several approaches to solve these issues are known from the prior art.

E.g. WO 2012/083094 A1 discloses that performing two back-to-backsynthesis runs of fluciclatide in quick succession on two differentcassettes is technically difficult due to the residual activity, towhich the operator would be exposed during spent-cassette dismountingprocedures. In order to shield the operating staff from this residualactivity on the cartridge during the short time required for thisdismounting procedure it is proposed in this document to provide ashielding collar specific for a separation cartridge used on thesynthesis cassette.

WO 2006/119226 A2 has disclosed an apparatus and method for makingradiopharmaceuticals, which synthesizer comprises a stationary processorhaving a disposable kit interface planar structure, a plurality ofrotary actuators and push-on fluidic connectors protruding from thisinterface, structure for releasably interfacing a disposable kit to theactuators and connectors, and associated disposable kit. Linearactuators translate the kit toward and after processing from supports onthe processor, so that the kit can fall in a suitable container.

One way of preparing multiple batches of radiopharmaceuticals, which maybe the same or different, is providing a number, e.g. four, ofsynthesizers in one or more hot cells, each synthesizer being controlledwith its own dedicated computer, PLC and so forth, including wastecontainers. Such a setup is spacious and expensive in view of shieldingand equipment.

SUMMARY OF THE INVENTION

The invention aims at providing a method and device for performing aplurality of synthesizing processes of preparing batches of one or moreradiopharmaceuticals in series, of which the expenses in equipment arereduced, while ensuring minimal involvement of operating staff andrelatively short downtime.

Another object of the invention is to provide such a method andsynthesizer allowing an economical waste management.

According to the invention a method of performing a plurality ofsynthesis processes of preparing a radiopharmaceutical in seriescomprises carrying out a first synthesis run comprising the steps of:

-   a) providing water containing 18F;-   b) trapping the 18F from the water provided in step a) on an anion    exchange material;-   c) eluting the trapped 18F from the anion exchange material to a    reaction vessel of a first radiopharmaceutical synthesis cassette;-   d) preparing a radiopharmaceutical incorporating the eluted 18F    using the first radiopharmaceutical synthesis cassette;-   wherein steps a)-d) are repeated in at least one subsequent run    using another radiopharmaceutical synthesis cassette; and-   wherein the method comprises a reconditioning step of said anion    exchange material between two consecutive runs.

In the method according to the invention a series of consecutivebatchwise synthesis processes of preparing a radiopharmaceutical isperformed using different radiopharmaceutical synthesis cassettes,except for the trapping of 18F supplied from the target, on ananion-exchanger and subsequent elution thereof. These trapping andelution steps are carried out using the same anion-exchanger materialand associated equipment for each synthesis of the series. Betweensubsequent runs the anion-exchanger is reconditioned. It has beendiscovered that reconditioning of the anion-exchanger can be performedrather easily, while maintaining its trapping capacity and withoutcross-contamination occurring. The method according to the inventionallows to install the equipment and chemicals for trapping, elution andreconditioning, preferably as a cassette, as well as the variouscassettes for the synthesis runs, which may be the same or different, inone time in a synthesizer, and to perform the various subsequentsynthesis runs without the need of accessing the hot cell, therebyavoiding the operator being exposed to residual activity. Thus thesubsequent runs are independent and do not need a full CIP operation orcleaning of a spent cassette. A main advantage is that the series ofprocesses can be controlled using a single server, router and PLC.Another important advantage is related to waste management. A singlerecovery bottle for 18O water suffices, as well as a single waste bottlefor the reconditioning solutions used for reconditioning theanion-exchanger. The waste liquids resulting from the subsequentsynthesis runs can be collected in a single waste bottle as well.Compared to the amount of waste produced upon a full CIP operation, thevolume of the spent reconditioning liquids is small in the methodaccording to the invention. This is beneficial in view of wastemanagement. Furthermore as the actual 18F labelling synthesis itself iscarried out each time on a fresh cassette, labelling yield does notsuffer from deterioration due to repeatedly cleaning. In addition reuseof the anion exchanging material reduces the costs of the series ofsynthesis reactions.

In the context of this application a cassette comprises theradiopharmaceutical synthesis process specific hardware components andchemicals required for performing the respective synthesis. For example,such a radiopharmaceutical synthesis cassette comprises one or moremanifolds provided with suitable valves that can be operated by asynthesizer, having a plurality of connections such as luer connectors,tubing, one or more reaction vessel(s) and vials containing thenecessary reagents and other liquids, optionally separation and/orpurification cartridges. Suitably the vials containing the necessaryreagents and other liquids may be obtained as a separate kit ofchemicals, while the other hardware components of the cassette areobtained as a pre-mounted assembly.

The design of the method also allows to use a compact synthesizer. E.g.a synthesizer for performing the method according to the inventionproducing three subsequent batches of 18F-FDG can be installed in asmall space having dimensions (width×height×depth) of 560 mm×420 mm×360mm.

A preferred anion exchange material comprises a quaternary ammoniumanion exchange material, in particular quaternary methyl ammonium (QMA),such as the silica-based ion exchanger cartridges loaded with QMA, e.g.Sep-Pak® Accell Plus QMA Plus Light Cartridge available from WatersCorporation, or Chromafix® PS-HCO3 available from MACHEREY-NAGEL GmbH &Co. KG. These QMA cartridges can be easily reconditioned using acarbonate solution. The carbonate concentration has appeared not verycritical. A suitable concentration is in the range of 0.01-5 M. Forexample, both a 1M and a 0.05 M K₂CO₃ solution have proven to allowsuccessful reconditioning. In a preferred embodiment the carbonatesolution is prepared in situ by diluting a concentrated carbonatesolution with water allowing to reduce the dimensions of the container(bottle) for the carbonate solution. E.g. a 1M K₂CO₃ solution can beeasily diluted with water for injection in the trapping, elution andreconditioning cassette by suitable operation.

A rinsing operation comprising one or more rinsing steps with only purewater can be used for reconditioning QMA as anion exchange material.However, pure water will not remove the metallic impurities derived fromthe target and also trapped on the QMA, and these impurities maybereleased by the eluent in a next elution step. Thus, using pure watermay cause cross-contamination between subsequent runs.

It is also possible to regenerate the anion exchange material with thepreferred eluent mixture itself (discussed hereinbelow), but due to thelow carbonate concentration thereof, the volume required forreconditioning will be higher than with a carbonate solution having ahigher concentration as exemplified above. The use of the preferredeluent mixture also as a reconditioning agent for reconditioning theanion exchange material will additionally result in waste of theexpensive crown ether (=phase transfer agent).

It is possible to elute the trapped 18F from the anion-exchanger usingonly an aqueous carbonate solution. Ammonia in water works as well.Suitably, in these cases a phase transfer agent is added to the reactionvessel in the synthesis cassette. Preferably the phase transfer agent isa crown ether like Kryptofix® 2.2.2., or a tetra alkyl ammonium salt.More preferably, the eluent is a mixture comprising carbonate, phasetransfer agent, water and acetonitrile.

A suitable example comprises a mixture of 0.7-7 mg of K₂CO₃, 0.3-1 mL ofCH₃CN, 5-30 mg of Kryptofix® 2.2.2. in 0.1-0.5 mL of H₂O. Here theamount of potassium carbonate can be replaced by Me_(x)H_(y)CO₃ whereinMe represents an alkali metal and x is 1-2 and x+y=2, such as Li₂CO₃,Cs₂CO₃, NaHCO₃, KHCO₃. Another suitable mixture is composed of 75 mMnBU₄NHCO₃, 750 μL H₂O, EtOH (stabilizer).

In this way the phase transfer agent and organic solvent likeacetonitrile for drying do not need to be part of the synthesiscassettes used for the actual production of the radiopharmaceutical inquestion.

The method according to the invention can be used for a variety ofradiopharmaceuticals based on 18F.

Examples include

-   18F-FDG ([18F]-fluoro-2-deoxyglucose),-   FMISO (1-(2-nitro-imidazolyl)-3-[18F]-fluoro-2-propanol;    1H-1-(3-[18F]-fluoro-2-hydroxypropyl)-2-nitroimidazole),-   NaF (sodium [18F]-fluoride),-   18F-FLT (3′-deoxy-3′-[18F] fluoro thymidine):-   18F-FET (O-(2-[18F]-fluoro ethyl)-L-tyrosine)-   18F-FES (16 α-[18F]fluoro-17 β-estradiol),-   FCHOL ([18F] fluorocholine)-   FACETATE ([18F] fluoroacetate)-   FDGal ([18F] fluorodeoxygalactose)-   F DOPA (L-6-[18F]fluoro-3,4-dihydroxyphenylalanine)-   18SFB (N-succinimidyl 4-[18F]fluorobenzoate).

Production of 18F-FDG is a preferred synthesis process.

As described hereinbefore, the subsequent synthesis runs can be directedto the preparation of radiopharmaceuticals, which may be the same ordifferent. In a preferred embodiment all subsequent synthesis runsproduce the same radiopharmaceutical.

According to a second aspect the invention provides a device forperforming a plurality of synthesis processes of preparing aradiopharmaceutical in series, in particular as explained above,comprising

-   a frame or housing-   an inlet for introducing water containing 18F;-   an anion-exchanger comprising an anionic exchange material connected    to said inlet;-   an eluent container comprising an eluent connected to said    anion-exchanger;-   a recondition container comprising a reconditioning agent connected    to said anion-exchanger,-   distribution means for selectively supplying eluted 18F to a    radiopharmaceutical synthesis cassette;-   at least two radiopharmaceutical synthesis cassettes, each cassette    being connected to said distribution means.

The frame or housing has the function of providing a structure formounting the other components, in particular the necessary tubes andother conduits including valves and actuators thereof, the reagents andwaste containers and cassettes. The radiopharmaceutical synthesiscassettes are as described above.

In a preferred embodiment thereof in the device according to theinvention the components, reagents necessary for trapping 18F, elutionthereof and reconditioning of the anionic exchange material arecontained in a ready-to-use cassette.

Advantageously the device according to the invention comprises a singleserver loaded with suitable software, router and PLC for inputting andselecting processes and controlling the device.

According to a third aspect the invention also provides a cassette foruse in the device according to the invention, which cassette comprises

-   at least one manifold provided with a plurality of valves    connectable to and operable by the device according to the invention-   an anion-exchanger comprising an anionic exchange material;-   an eluent container comprising an eluent-   a recondition container comprising a reconditioning agent.

The anion-exchanger, eluent container and recondition container areconnectable to the at least one manifold.

In a preferred embodiment thereof the recondition container contains aconcentrated carbonate solution, and the cassette also is provided witha container comprising water.

The advantages as explained above with respect to the method accordingto the invention are applicable in a similar way to the device andcassette according to the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be illustrated by reference to the attached drawings,wherein:

FIG. 1 shows a diagrammatic view of a part of a synthesizer, inparticular a cassette suitable for trapping 18F, eluting andreconditioning;

FIG. 2 shows an example of a process scheme for performing a number ofsynthesis processes according to the invention; and

FIG. 3 shows a diagrammatic view of a synthesizer for performing anumber of synthesis processes according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

In FIG. 1 a part of a synthesizer being an embodiment of a disposablereconditioning cassette according to the invention, for trapping 18F onan anionic exchange material, subsequent elution and reconditioning ofthe anion exchange material, is shown diagrammatically. In theembodiment shown the cassette indicated in its entirety by referencenumeral 10, comprises a first manifold 12 and a second manifold 14. Eachmanifold 12, 14 comprises five 3way valves 16, individually indicated 16a through 16 e, and 16 f-16 j respectively. These reference numerals arealso used to indicate the respective positions. The valves 16 arepreferably operated by compressed air as disclosed in WO 2013/127439 A1,which is incorporated by reference. Typically connections with tubingoccurs by luerlock connectors 17, while (reagent) vials and otherbottles are usually closed by suitable septums 19 that are spiked.

Water containing 18F is derived from a cyclotron (not shown) andintroduced at 16 j and trapped on anion-exchanger 18, such as a Sep-PakAccell Plus QMA Carbonate Plus Light cartridge available from WatersCorporation, which is connected to the right hand ends 20, 22 ofmanifolds 12 and 14 via tubing 24. The water is removed at 16 e andcollected into a bottle or other container (not shown). Once the 18F istrapped by anion-exchanger 18 an eluent, typically a mixture of(potassium) carbonate, a transfer agent like Kryptofix, water andacetonitrile, from vial 26 is metered in syringe 28 via valves 16 d, 16a and then passed over the anion-exchanger 18 thereby extracting the 18Fand sending it to a reaction vessel of one of the synthesis cassettes(see FIG. 3) at valves 16 f-h. The left end 30 of manifold 12 isconnected to a source of an inert gas such as nitrogen or helium.

For reconditioning the anion-exchanger 18 reconditioning agent,typically an aqueous carbonate solution, is used. In the embodimentshown in FIG. 1, this solution is prepared in situ in syringe 28 from ahigh molar K2CO3 solution in vial 32 at position 16 c and water frombottle 34 at position 16 b. It will be recognized that the vials 26, 32,34 can be placed in any order. Then the diluted K₂CO₃ solution thusprepared is ejected from syringe 28 over anion-exchanger 18 to a wastebottle (not shown) connected to the left hand end 36 at position 16 f ofmanifold 14. Subsequently one or more rinsing steps are carried out withwater from bottle 34 using syringe 28. The spent water is collected inthe same waste bottle at 36. The anion-exchanger 18 is dried using theinert gas introduced at 30. The water at 16 i is used for each synthesisstep requiring water, that is to say water is sampled from 16 i forsubsequent synthesis runs. Cross-contamination is not possible becausethe water arrives from 16 f g h in the different runs.

FIG. 2 shows an example of a process scheme for performing multiplereactions in series.

The series of reactions start with supply of 18F in water from a targetand trapping thereof on the anion-exchanger. Then the trapped 18F iseluted to radiopharmaceutical synthesis process 1. The anion-exchangeris reconditioned. Thereafter the sequence of steps A) through D) isrepeated using the same anion-exchanger, but the eluted 18F is nowguided to a second synthesis process 2. Upon finishing this synthesisprocess, the anion-exchanger is reconditioned once more, and thesequence of steps A) through D) is repeated for the last time.

FIG. 3 shows an embodiment of a synthesizer 48 having a frame or housing49 allowing insertion of cassettes, wherein 3 consecutive batches of18F-FDG are prepared using—in this embodiment—identicalradiopharmaceutical synthesis cassettes 50 (diagrammatically shown inbroken lines). Each cassette comprises two manifold 52 and 54, and eachmanifold has five 3way valves 56 (or positions), numbered 56 a-e and 56f-j respectively. In the top left part of the synthesizer the eluentmixture containing 18F is prepared as explained above with reference toFIG. 1. This eluent mixture is used in the first synthesis process of18F-FDG. The eluent mixture is introduced in a cassette 50′ at position56 c and collected in reactor vessel 58, which can be heated by heatingmeans (not shown). Therein the eluent mixture comprising 18F is driedusing acetonitrile from bottle 60. Waste is collected at left hand end62 of manifold 54. Precursor is added from vial 64 at position 56 d.After reaction the thus produced intermediate product, after dilutionwith water sampled in 16 i is separated on a suitable solid phaseextraction cartridge 66 at position 56 j and eluted back into thereaction vessel 58 using a suitable eluent such as EtOH from vial 68 atposition 56 i. If the chemistry allows so, the water container or bagmay be incorporated in the radiopharmaceutical synthesis cassette 50,50′ or 50″. The protective groups of the intermediate product areremoved by means of basic hydrolysis using NaOH contained in syringe 70at position 56 g. The final product after buffering with buffer fromvial 72 at position 56 f is removed via valve 56 h for subsequentformulation and quality control. After approval it can be used fordiagnosis purposes. The syringe on position 56 a is used for thepressurization of vials 60, 64, 72, 68, and for sampling of chemicalssolutions, for dilution of reactive bulk mixture, and loading of theseparation cartridges.

After this first production run the reconditioning of theanion-exchanger 18 is performed as outlined above with respect toFIG. 1. Fresh 18F containing water is again trapped on the thusreconditioned anion exchanger 18 and subsequently eluted to the secondsynthesis process cassette 50″, where 18F-FDG is produced in the sameway as described with respect to cassette 50′. Also after this secondproduction run reconditioning of the anion-exchanger takes place. Then athird batch of eluent mixture containing 18F is prepared and used insynthesis process 3 in cassette 50′″.

The synthesizer 48 is operated by a single control system 80 comprisingPLC, router and server (PC).

In an embodiment of the synthesizer 48 the cassette 10 and cassettes50′, 50″ and 50′″ are releasibly mounted on a fixed upright front plateof the frame or housing 49, while common pumps, drivers and otherelectronics and the like are mounted on a detachable upright rear plate(not visible in FIG. 3). For example the rear plate is connected to theframe or housing 49 using removable hinges, that are horizontallyarranged at the bottom. For access to the components on the rear plateit is rotated backwards over a certain angle allowing inspection,servicing and maintenance of the components, while hooks or otherconnecting elements maintain the rear plate in this inclined position.Upon detachment of these hooks, the rear plate can rotate further downto an essentially horizontal position. In this position the rear platecan be removed as a module from the synthesizer.

The invention claimed is:
 1. A method of performing a plurality ofsynthesis processes of preparing a radiopharmaceutical in series, whichmethod comprises carrying out a first synthesis run comprising the stepsof: a) providing water containing 18F; b) trapping the 18F from thewater provided in step a) on an anion exchange material; c) eluting thetrapped 18F from the anion exchange material to a reaction vessel of afirst radiopharmaceutical synthesis cassette; d) preparing aradiopharmaceutical incorporating the eluted 18F using the firstradiopharmaceutical synthesis cassette; wherein steps a)-d) are repeatedin at least one subsequent run using another radiopharmaceuticalsynthesis cassette; and wherein the method comprises a reconditioningstep of said anion exchange material between two consecutive runs saidreconditioning step comprises treating the anion exchange material witha carbonate solution.
 2. The method according to claim 1, wherein saidanion exchange material is a quaternary ammonium anion exchangematerial.
 3. The method according to claim 1, wherein the carbonatesolution is prepared in situ by diluting a concentrated carbonatesolution with water.
 4. The method according to claim 1, wherein in stepc) the eluent comprises a phase transfer agent.
 5. The method accordingto claim 1, wherein the radiopharmaceutical is selected from the groupof FDG, FMISO, NaF, FLT, FET, FES, FCHOL, FACETATE, FDGal, FDOPA, SFB.6. The method according to claim 1, wherein at least one process of saidplurality of synthesis processes comprises preparing 18FDG.